In the United States obesity rates are increasing, and understanding the molecular and cellular basis for breast cancer associated with obesity is of significant clinical relevance and impact. Obese women are more likely to be diagnosed with non-familial estrogen receptor negative tumors than lean women, and these tumors are more likely to be associated with nodal metastases. Since breast stromal tissue is a reservoir of subcutaneous fat the stromal tissue microenvironment is known to have a profound effects on breast cancer development and progression, the changes that take place within the fat depots of obese individuals may play a significant role in the pathogenesis of breast cancer. Therefore, elucidating the mechanistic role of adipocytes and adipose tissue biology in breast cancer is critical for prevention and treatment of obesity-related cancer. Fat cells within the breast tissue of obese women secrete a monocyte chemo-attractant protein-1 (MCP-1) that promotes the recruitment of macrophages into breast adipose tissue. These cells when recruited induce local tissue inflammation, but role of macrophages in obesity-associated inflammation during is currently unknown. Here, we aim to test from bench to human clinical trials, the hypothesis that breast tissue in obese women exhibits increased neoangiogenesis and inflammation prior to overt tumor formation due to the recruitment of macrophages by MCP-1 producing adipocytes, thereby leading to increased vascularity and malignancy. In Aim 1 of this project, we will investigate the molecular mechanism by which bone marrow-derived macrophages promote obesity-induced angiogenesis and cancer initiation. Aim 2 will test whether bone marrow-derived macrophages are necessary for obesity-induced tumor progression, and Aim 3 will determine whether obesity-induced preneoplastic changes can be reversed. Our studies provide innovative insight as to why obesity is associated with increased cancer incidence and aggressiveness. In addition, this work will provide a novel paradigm for the prophylactic treatment of high risk obese patients. PUBLIC HEALTH RELEVANCE: This investigator initiated research grant seeks to investigate from pre-clinical models to community partnered trials, the relationship between obesity and the initiation and aggressive behavior of ER- breast cancer in Caucasian and African American women. This is in response to Provocative Question (PQ1) How does obesity contribute to cancer risk?